{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T12:24:28Z","timestamp":1793103868824,"version":"4.5.0"},"reference-count":40,"publisher":"American Medical Association (AMA)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2023,6,1]]},"abstract":"<jats:sec id=\"ab-noi230013-4\"><jats:title>Importance<\/jats:title><jats:p>Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown.<\/jats:p><\/jats:sec><jats:sec id=\"ab-noi230013-5\"><jats:title>Objective<\/jats:title><jats:p>To test the association between pathogenic somatic variants in the hippocampus and MTLE.<\/jats:p><\/jats:sec><jats:sec id=\"ab-noi230013-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy\u2013associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022.<\/jats:p><\/jats:sec><jats:sec id=\"ab-noi230013-7\"><jats:title>Exposures<\/jats:title><jats:p>Drug-resistant MTLE.<\/jats:p><\/jats:sec><jats:sec id=\"ab-noi230013-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex.<\/jats:p><\/jats:sec><jats:sec id=\"ab-noi230013-9\"><jats:title>Results<\/jats:title><jats:p>Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; <jats:italic>P<\/jats:italic>\u2009=\u2009.01) were detected in patients with MTLE but not in controls. Ten of these variants were in <jats:italic>PTPN11<\/jats:italic>, <jats:italic>SOS1<\/jats:italic>, <jats:italic>KRAS<\/jats:italic>, <jats:italic>BRAF<\/jats:italic>, and <jats:italic>NF1<\/jats:italic>, all predicted to constitutively activate Ras\/Raf\/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1\/2 phosphorylation, indicative of Ras\/Raf\/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the <jats:italic>PTPN11<\/jats:italic> variants as a possible dominant gain-of-function mechanism.<\/jats:p><\/jats:sec><jats:sec id=\"ab-noi230013-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>Hippocampal somatic variants, particularly those activating Ras\/Raf\/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaneurol.2023.0473","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T15:00:47Z","timestamp":1682953247000},"page":"578","source":"Crossref","is-referenced-by-count":85,"title":["Contribution of Somatic Ras\/Raf\/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy"],"prefix":"10.1001","volume":"80","author":[{"given":"Sattar","family":"Khoshkhoo","sequence":"first","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"},{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilan","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Chahine","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. Zeynep","family":"Erson-Omay","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie M.","family":"Robert","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emre","family":"Kiziltug","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eyiyemisi C.","family":"Damisah","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Nelson-Williams","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangya","family":"Zhu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenna","family":"Kong","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"August Yue","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Stronge","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Westley","family":"Phillips","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian H.","family":"Chhouk","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Bizzotto","sequence":"additional","affiliation":[{"name":"Sorbonne University, Paris Brain Institute (ICM), National Institute of Health and Medical Research (INSERM), National Center for Scientific Research (CNRS), Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiuni N.","family":"Adikari","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimeng","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Witkowski","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dulcie","family":"Lai","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Lokan","sequence":"additional","affiliation":[{"name":"Department of Anatomical Pathology, Austin Health, Heidelberg, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid E.","family":"Scheffer","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Australia"},{"name":"Murdoch Children\u2019s Research Institute, Parkville, Australia"},{"name":"Florey Institute of Neuroscience and Mental Health, Heidelberg, Australia"},{"name":"Department of Pediatrics, University of Melbourne, Royal Children\u2019s Hospital, Parkville, Australia"},{"name":"Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel F.","family":"Berkovic","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Australia"},{"name":"Bladin-Berkovic Comprehensive Epilepsy Program, Department of Neurology, Austin Health, Heidelberg, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shozeb","family":"Haider","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Department of Medicine (Austin Health), University of Melbourne, Heidelberg, Australia"},{"name":"Murdoch Children\u2019s Research Institute, Parkville, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Gunel","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Lifton","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine, New Haven, Connecticut"},{"name":"Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. Mark","family":"Richardson","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Massachusetts General Hospital, Boston"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingmar","family":"Bl\u00fcmcke","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University Hospitals Erlangen, Erlangen, Germany"},{"name":"Epilepsy Center, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanda","family":"Alexandrescu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Huttner","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin L.","family":"Heinzen","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill"},{"name":"Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jidong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annapurna","family":"Poduri","sequence":"additional","affiliation":[{"name":"Epilepsy Genetics Program, Division of Epilepsy and Neurophysiology, Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihal","family":"DeLanerolle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis D.","family":"Spencer","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunjung Alice","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Department of Pediatrics, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Walsh","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Department of Neurology and Pediatrics, Harvard Medical School, Boston, Massachusetts"},{"name":"Allen Discovery Center for Human Brain Evolution, Boston Children\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"},{"name":"Howard Hughes Medical Institute, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Broad Institute of MIT and Harvard, Cambridge, Massachusetts"},{"name":"Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, New York"},{"name":"Department of Neurosurgery, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"1","key":"noi230013r1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1212\/WNL.0b013e318204a36a","article-title":"Estimating risk for developing epilepsy: a population-based study in Rochester, Minnesota.","volume":"76","author":"Hesdorffer","year":"2011","journal-title":"Neurology"},{"issue":"9","key":"noi230013r2","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1016\/S1474-4422(20)30220-9","article-title":"Seizure outcome and use of antiepileptic drugs after epilepsy surgery according to histopathological diagnosis: a retrospective multicentre cohort study.","volume":"19","author":"Lamberink","year":"2020","journal-title":"Lancet Neurol"},{"issue":"2","key":"noi230013r3","doi-asserted-by":"publisher","first-page":"220","DOI":"10.3171\/jns.1995.82.2.0220","article-title":"Influence of the type of initial precipitating injury and at what age it occurs on course and outcome in patients with temporal lobe seizures.","volume":"82","author":"Mathern","year":"1995","journal-title":"J Neurosurg"},{"issue":"11","key":"noi230013r4","doi-asserted-by":"publisher","first-page":"1611","DOI":"10.1001\/archneur.57.11.1611","article-title":"Neurophysiologic and neuroradiologic features of intractable epilepsy after traumatic brain injury in adults.","volume":"57","author":"Diaz-Arrastia","year":"2000","journal-title":"Arch Neurol"},{"issue":"5","key":"noi230013r5","doi-asserted-by":"publisher","first-page":"546","DOI":"10.1038\/ng.2599","article-title":"Mutations in DEPDC5 cause familial focal epilepsy with variable foci.","volume":"45","author":"Dibbens","year":"2013","journal-title":"Nat Genet"},{"issue":"3","key":"noi230013r6","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/ng832","article-title":"Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features.","volume":"30","author":"Kalachikov","year":"2002","journal-title":"Nat Genet"},{"issue":"6","key":"noi230013r7","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1016\/j.ajhg.2015.04.020","article-title":"Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.","volume":"96","author":"Dazzo","year":"2015","journal-title":"Am J Hum Genet"},{"issue":"8896","key":"noi230013r8","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1016\/S0140-6736(94)91463-X","article-title":"Autosomal dominant frontal epilepsy misdiagnosed as sleep disorder.","volume":"343","author":"Scheffer","year":"1994","journal-title":"Lancet"},{"issue":"8","key":"noi230013r9","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.braindev.2011.10.008","article-title":"Genetics of temporal lobe epilepsy.","volume":"34","author":"Hwang","year":"2012","journal-title":"Brain Dev"},{"key":"noi230013r10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.eplepsyres.2017.02.001","article-title":"Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy.","volume":"131","author":"Perucca","year":"2017","journal-title":"Epilepsy Res"},{"issue":"3","key":"noi230013r11","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000245","article-title":"Rare variants and de novo variants in mesial temporal lobe epilepsy with hippocampal sclerosis.","volume":"4","author":"Wong","year":"2018","journal-title":"Neurol Genet"},{"issue":"17","key":"noi230013r12","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1212\/WNL.0000000000002608","article-title":"A targeted resequencing gene panel for focal epilepsy.","volume":"86","author":"Hildebrand","year":"2016","journal-title":"Neurology"},{"key":"noi230013r13","doi-asserted-by":"publisher","first-page":"515","DOI":"10.3389\/fneur.2018.00515","article-title":"Molecular genetic characterization of patients with focal epilepsy using a customized targeted resequencing gene panel.","volume":"9","author":"Tsai","year":"2018","journal-title":"Front Neurol"},{"issue":"2","key":"noi230013r14","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.ajhg.2019.05.020","article-title":"Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals.","volume":"105","author":"Feng","year":"2019","journal-title":"Am J Hum Genet"},{"issue":"13","key":"noi230013r15","doi-asserted-by":"publisher","first-page":"3754","DOI":"10.1016\/j.celrep.2017.11.106","article-title":"Somatic mutations activating the mTOR pathway in dorsal telencephalic progenitors cause a continuum of cortical dysplasias.","volume":"21","author":"D\u2019Gama","year":"2017","journal-title":"Cell Rep"},{"issue":"6","key":"noi230013r16","doi-asserted-by":"publisher","first-page":"1133","DOI":"10.1002\/ana.v83.6","article-title":"Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy.","volume":"83","author":"Winawer","year":"2018","journal-title":"Ann Neurol"},{"issue":"W1","key":"noi230013r17","doi-asserted-by":"publisher","first-page":"W317","DOI":"10.1093\/nar\/gkab447","article-title":"KOBAS-i: intelligent prioritization and exploratory visualization of biological functions for gene enrichment analysis.","volume":"49","author":"Bu","year":"2021","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"noi230013r18","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence.","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"noi230013r19","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.1038\/s41467-021-22125-z","article-title":"The origins and genetic interactions of KRAS mutations are allele- and tissue-specific.","volume":"12","author":"Cook","year":"2021","journal-title":"Nat Commun"},{"issue":"2","key":"noi230013r20","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1158\/1541-7786.MCR-18-0777","article-title":"PTPN11 plays oncogenic roles and is a therapeutic target for BRAF wild-type melanomas.","volume":"17","author":"Hill","year":"2019","journal-title":"Mol Cancer Res"},{"issue":"6892","key":"noi230013r21","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1038\/nature00766","article-title":"Mutations of the BRAF gene in human cancer.","volume":"417","author":"Davies","year":"2002","journal-title":"Nature"},{"issue":"6","key":"noi230013r22","doi-asserted-by":"publisher","first-page":"793","DOI":"10.3390\/brainsci11060793","article-title":"The role of KRAS mutations in cortical malformation and epilepsy surgery: a novel report of nevus sebaceous syndrome and review of the literature.","volume":"11","author":"Pepi","year":"2021","journal-title":"Brain Sci"},{"issue":"8","key":"noi230013r23","doi-asserted-by":"publisher","first-page":"2704","DOI":"10.1093\/brain\/awac117","article-title":"Somatic variants in diverse genes leads to a spectrum of focal cortical malformations.","volume":"145","author":"Lai","year":"2022","journal-title":"Brain"},{"issue":"12","key":"noi230013r24","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/nrneurol.2016.173","article-title":"Low-grade epilepsy-associated neuroepithelial tumours\u2014the 2016 WHO classification.","volume":"12","author":"Bl\u00fcmcke","year":"2016","journal-title":"Nat Rev Neurol"},{"issue":"3","key":"noi230013r25","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1086\/515504","article-title":"Confirmation of a double-hit model for the NF1 gene in benign neurofibromas.","volume":"61","author":"Serra","year":"1997","journal-title":"Am J Hum Genet"},{"issue":"2","key":"noi230013r26","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.cell.2020.09.002","article-title":"Phase separation of disease-associated SHP2 mutants underlies MAPK hyperactivation.","volume":"183","author":"Zhu","year":"2020","journal-title":"Cell"},{"issue":"3","key":"noi230013r27","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1056\/NEJMoa1709449","article-title":"Somatic activating KRAS mutations in arteriovenous malformations of the brain.","volume":"378","author":"Nikolaev","year":"2018","journal-title":"N Engl J Med"},{"issue":"4","key":"noi230013r28","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.stem.2018.03.015","article-title":"Human hippocampal neurogenesis persists throughout aging.","volume":"22","author":"Boldrini","year":"2018","journal-title":"Cell Stem Cell"},{"issue":"10","key":"noi230013r29","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1523\/JNEUROSCI.17-10-03727.1997","article-title":"Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus.","volume":"17","author":"Parent","year":"1997","journal-title":"J Neurosci"},{"issue":"4","key":"noi230013r30","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/1097-4547(20010215)63:4<313::AID-JNR1025>3.0.CO;2-4","article-title":"Enhanced neurogenesis in the rodent hippocampus following traumatic brain injury.","volume":"63","author":"Dash","year":"2001","journal-title":"J Neurosci Res"},{"issue":"6417","key":"noi230013r31","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1126\/science.aau3879","article-title":"Somatic mutant clones colonize the human esophagus with age.","volume":"362","author":"Martincorena","year":"2018","journal-title":"Science"},{"issue":"11","key":"noi230013r32","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1038\/s41591-018-0172-x","article-title":"BRAF somatic mutation contributes to intrinsic epileptogenicity in pediatric brain tumors.","volume":"24","author":"Koh","year":"2018","journal-title":"Nat Med"},{"issue":"6","key":"noi230013r33","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1523\/JNEUROSCI.4077-13.2014","article-title":"RAS\/ERK signaling controls proneural genetic programs in cortical development and gliomagenesis.","volume":"34","author":"Li","year":"2014","journal-title":"J Neurosci"},{"issue":"3","key":"noi230013r34","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/nn.3933","article-title":"Pathway-driven discovery of epilepsy genes.","volume":"18","author":"Noebels","year":"2015","journal-title":"Nat Neurosci"},{"issue":"1","key":"noi230013r35","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcaa235","article-title":"Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain.","volume":"3","author":"Ye","year":"2021","journal-title":"Brain Commun"},{"issue":"6","key":"noi230013r36","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1002\/ana.26080","article-title":"Detection of brain somatic mutations in cerebrospinal fluid from refractory epilepsy patients.","volume":"89","author":"Kim","year":"2021","journal-title":"Ann Neurol"},{"issue":"23","key":"noi230013r37","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1212\/WNL.0000000000201469","article-title":"Somatic mosaic pathogenic variant gradient detected in trace brain tissue from stereo-EEG depth electrodes.","volume":"99","author":"Ye","year":"2022","journal-title":"Neurology"},{"key":"noi230013r38","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.yebeh.2014.12.027","article-title":"Perceptions of epilepsy surgery: a systematic review and an explanatory model of decision-making.","volume":"44","author":"Dewar","year":"2015","journal-title":"Epilepsy Behav"},{"issue":"9","key":"noi230013r39","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/S1474-4422(16)30141-7","article-title":"Surgery for epilepsy: the need for global acceptance and access.","volume":"15","author":"Warf","year":"2016","journal-title":"Lancet Neurol"},{"issue":"11","key":"noi230013r40","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a031492","article-title":"Targeting the MAPK Pathway in RAS Mutant Cancers.","volume":"8","author":"Hymowitz","year":"2018","journal-title":"Cold Spring Harb Perspect Med"}],"container-title":["JAMA Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamaneurology\/articlepdf\/2804531\/jamaneurology_khoshkhoo_2023_oi_230013_1686342415.49452.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T15:05:18Z","timestamp":1686582318000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamaneurology\/fullarticle\/2804531"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,1]]},"references-count":40,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2023,6,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamaneurol.2023.0473","relation":{},"ISSN":["2168-6149"],"issn-type":[{"value":"2168-6149","type":"print"}],"subject":[],"published":{"date-parts":[[2023,6,1]]}}}